ES2590038T3 - Oxazine derivative - Google Patents

Abstract

A compound of formula (1): ** Formula ** wherein ring A is a substituted carbocycle or a substituted or unsubstituted heterocycle, R1 is substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted acyl, cyano, carboxy, substituted or unsubstituted alkoxycarbonyl, substituted or unsubstituted alkenyloxycarbonyl, substituted or unsubstituted alkynyloxycarbonyl or substituted or unsubstituted carbamoyl, substituted or unsubstituted thiocarbamoyl, a substituted or unsubstituted carbocyclic group, a group substituted or unsubstituted heterocyclic, R2a and R2b are each independently hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted acyl, substituted or unsubstituted alkoxycarbonyl or substituted or unsubstituted carbamoyl, in which Rza and Rzb are each one independently, hydrogen, halogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, alkyne substituted or unsubstituted yl, substituted or unsubstituted alkoxy, substituted or unsubstituted alkenyloxy, substituted or unsubstituted alkynyloxy, substituted or unsubstituted alkylthio, substituted or unsubstituted alkenylthio, substituted or unsubstituted alkynylthio, substituted or unsubstituted acyl, carboxy, substituted or unsubstituted alkoxycarbonyl, substituted or unsubstituted alkenyloxycarbonyl, substituted or unsubstituted alkynyloxycarbonyl, substituted or unsubstituted amino, substituted or unsubstituted carbamoyl, substituted or unsubstituted thiocarbamoyl, a substituted or unsubstituted carbocyclic group, substituted or unsubstituted carbocyclyloxy substituted or unsubstituted carbocyclyl, substituted or unsubstituted carbocyclyl alkyl. substituted or unsubstituted carbocyclylalkoxy, substituted or unsubstituted carbocyclyloxycarbonyl, a substituted or unsubstituted heterocyclic group, substituted or unsubstituted heterocyclyloxy, substituted or unsubstituted heterocyclylthio, substituted or unsubstituted heterocyclylalkyl, unsubstituted heterocyclic or unsubstituted heterocyclyl or Rza and Rzb, together with the carbon atom to which they are attached, can form a substituted or unsubstituted non-aromatic carbocycle or a substituted or unsubstituted non-aromatic heterocycle, R3a, R3b, R3c, R4a, R4b and R4c are, each one independently, hydrogen, halogen, hydroxy, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted alkoxy, substituted or unsubstituted alkenyloxy or substituted or unsubstituted alkynyloxy, substituted or unsubstituted alkylthio , substituted or unsubstituted alkenylthio, substituted alkylthio unsubstituted or substituted, substituted or unsubstituted acyl, substituted or unsubstituted acyloxy, cyano, nitro, carboxy, substituted or unsubstituted alkoxycarbonyl, substituted or unsubstituted alkenyloxycarbonyl, substituted or unsubstituted alkynyloxycarbonyl, substituted or unsubstituted amino, substituted carbamoyl or unsubstituted, substituted or unsubstituted thiocarbamoyl, substituted or unsubstituted sulfamoyl, substituted or unsubstituted alkylsulfinyl, substituted or unsubstituted alkenylsulfinyl, substituted or unsubstituted alkylsulfinyl, substituted or unsubstituted alkylsulfonyl, substituted or unsubstituted alkenylsulfonyl, alkylsulfonyl , a substituted or unsubstituted carbocyclic group, substituted or unsubstituted carbocyclyloxy, substituted or unsubstituted carbocyclylthio, substituted or unsubstituted carbocyclylalkyl, substituted or unsubstituted carbocyclylalkoxy, substituted or unsubstituted carbocyclyloxycarbonyl, substituted carbocyclylsulfinyl or unsubstituted, substituted or unsubstituted carbocyclylsulfonyl, a substituted or unsubstituted heterocyclic group, substituted or unsubstituted heterocyclyloxy, substituted or unsubstituted heterocyclylthio, substituted or unsubstituted heterocyclylalkyl, substituted or unsubstituted heterocyclyloxycarbonyloxycarbonyloxy or unsubstituted or substituted or unsubstituted heterocyclylsulfonyl, substituted, unsubstituted or substituted heterocyclyloxycarbonyl, substituted or unsubstituted heterocyclylsulfinyl or substituted or unsubstituted heterocyclylsulfonyl, R3a and R3b, together with the carbon atom to which they are attached, can form a substituted carbocycle or unsubstituted or a substituted or unsubstituted heterocycle, R4a and R4b, together with the carbon atom to which they are attached, can form a substituted or unsubstituted carbocycle or a substituted or unsubstituted heterocycle, the Q ring is a substituted carbocycle or no substitute uido, or a substituted or unsubstituted heterocycle, the broken line a, the broken line b and the broken line c each independently means the presence or absence of a link, when a broken line a means the presence of a link, then R3b and R4b are absent, when the dashed line b means the presence of a link, then R3c is absent when the dashed line c means the presence of a link, then R4c is absent, Y1 and Y2 are, each independently, -C (R5) (R6) -, -C (R6)> =, -N (R7) -, -N> =, -S-, -SO-, -SO2- or -O-, Y3 and Y4 are, each one independently, -C (R5) (R6) -, N (R7) -, -S-, -SO-, -SO2- or -O-, R5 and R6 are each independently hydrogen, halogen, hydroxy, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted alkoxy, substituted or unsubstituted alkenyloxy, substituted or unsubstituted alkynyloxy, alkyl substituted or unsubstituted thio, substituted or unsubstituted alkenylthio, substituted or unsubstituted alkynylthio, substituted or unsubstituted acyl, substituted or unsubstituted acyloxy, cyano, nitro, carboxy, substituted or unsubstituted alkoxycarbonyl, substituted or unsubstituted alkenyloxycarbonyl, alkynyloxycarbonyl, substituted or unsubstituted amino, substituted or unsubstituted carbamoyl, substituted or unsubstituted thiocarbamoyl, substituted or unsubstituted sulfamoyl, substituted or unsubstituted alkylsulfinyl, substituted or unsubstituted alkenylsulfinyl, substituted or unsubstituted alkylsulfinyl, substituted or unsubstituted alkylsulphonyl, alkenyl or unsubstituted, substituted or unsubstituted alkylsulfonyl, a substituted or unsubstituted carbocyclic group, substituted or unsubstituted carbocyclyloxy, substituted or unsubstituted carbocyclylthio, substituted or unsubstituted carbocyclylalkyl, substituted or unsubstituted carbocyclylalkoxy, carbocyclyloxycarbon substituted or unsubstituted ilo, substituted or unsubstituted carbocyclylsulfinyl, substituted or unsubstituted carbocyclylsulfonyl, a substituted or unsubstituted heterocyclic group, substituted or unsubstituted heterocyclyloxy, substituted or unsubstituted heterocyclylthio, substituted or unsubstituted heterocyclyl, substituted heterocyclyl substituted or unsubstituted heterocyclyloxycarbonyl, substituted or unsubstituted heterocyclylsulfinyl, substituted or unsubstituted heterocyclylsulfonyl and R7 is hydrogen, halogen, hydroxy, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted alkoxy, substituted or unsubstituted alkenyloxy, substituted or unsubstituted alkynyloxy, substituted or unsubstituted acyl, substituted or unsubstituted acyloxy, cyano, nitro, carboxy, substituted or unsubstituted alkoxycarbonyl, substituted or unsubstituted alkenyloxycarbonyl, substituted alkyloxycarbonyl oo unsubstituted, substituted or unsubstituted alkylsulfinyl, substituted or unsubstituted alkenylsulfinyl, substituted or unsubstituted alkylsulfinyl, substituted or unsubstituted alkylsulphonyl, substituted or unsubstituted alkenylsulfonyl, substituted or unsubstituted alkylsulfonyl, substituted or unsubstituted carbamoyl, thio substituted, substituted or unsubstituted sulfamoyl, substituted or unsubstituted amino, a substituted or unsubstituted carbocyclic group, substituted or unsubstituted carbocyclyloxy, substituted or unsubstituted carbocyclylthio, substituted or unsubstituted carbocyclylalkyl, substituted or unsubstituted carbocyclylalkoxy, unsubstituted carbocyclyloxy substituted, substituted or unsubstituted carbocyclylsulfinyl, substituted or unsubstituted carbocyclylsulfonyl, a substituted or unsubstituted heterocyclic group, substituted or unsubstituted heterocyclyloxy, substituted or unsubstituted heterocyclylthio, substituted or heterocyclyl alkyl unsubstituted, substituted or unsubstituted heterocyclylalkoxy, substituted or unsubstituted heterocyclyloxycarbonyl, substituted or unsubstituted heterocyclylsulfinyl or substituted or unsubstituted heterocyclylsulfonyl, substituents of "substituted carbocycle" and "substituted or unsubstituted heterocycle" in ring A, ring A 'and ring B are, if present, one or more substituents selected from a group selected from the substituent group α; wherein the substituent group α is a group consisting of halogen, hydroxy, alkoxy, haloalkoxy, hydroxyalkoxy, alkoxyalkoxy, acyl, acyloxy, carboxy, alkoxycarbonyl, amino, acylamino, alkylamino, imino, hydroxyimino, alkoxyimino, alkylthio, carbamoyl, alkylcarbamoyl, hydroxyalkylcarbamoyl, sulfamoyl, alkylsulfamoyl, alkylsulfinyl, alkylsulphonylamino, alkylsulfonylalkyl amino, alkylsulfonylimino, alkylsulfinylamino, alkylsulfinyl alkylamino, alkylsulfinylimino, cyano, nitro, a carbocyclic group and a heterocyclic groups with one or more of which are substituted for one or more of which one is selected from each one halogen, alkyl, hydroxy and alkoxy: alkyl substituted with one or more groups selected from the substituent group α, hydroxyimino and alkoxyimino, or

Description

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Y1 and Y2 are each independently -C (R5) (R6) -, -C (R5) =, -N (R7) -, -N =, -S-, -SO-, -SO2-u - O-, Y3 and Y4 are each independently -C (R5) (R6) -, -C (R5) =, -N (R7) -, -S-, -SO-, -SO2-u -O -, R5 and R6 are each independently hydrogen, halogen, hydroxy, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted alkoxy, substituted or unsubstituted alkynyloxy substituted, substituted or unsubstituted alkylthio, substituted or unsubstituted alkenylthio, substituted or unsubstituted alkynylthio, substituted or unsubstituted acyl, substituted or unsubstituted acyloxy, cyano, nitro, carboxy, substituted or unsubstituted alkoxycarbonyl, substituted or unsubstituted alkenyloxycarbonyl, substituted or unsubstituted alkynyloxycarbonyl, substituted or unsubstituted amino, substituted or unsubstituted carbamoyl, substituted or unsubstituted thiocarbamoyl, substituted or non-substituted sulfamoyl ituido, substituted or unsubstituted alkylsulfinyl, substituted or unsubstituted alkenylsulfinyl, substituted or unsubstituted alkylsulfinyl, substituted or unsubstituted alkylsulfonyl, substituted or unsubstituted alkenylsulfonyl, substituted or unsubstituted alkylsulfonyl, a substituted or unsubstituted carbocyclic group, carbocyclic substituted, substituted or unsubstituted carbocyclylthio, substituted or unsubstituted carbocyclyloxycarbonyl, substituted or unsubstituted carbocyclylsulfinyl, substituted or unsubstituted carbocyclylsulfonyl, a substituted or unsubstituted heterocyclic group, substituted or unsubstituted heterocyclyloxy substituted or unsubstituted heterocyclyloxy substituted, substituted or unsubstituted heterocyclylsulfinyl, substituted or unsubstituted heterocyclylsulfonyl, and R7 is hydrogen, halogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl or, substituted or unsubstituted alkoxy, substituted or unsubstituted alkenyloxy, substituted or unsubstituted alkynyloxy, substituted or unsubstituted acyl, substituted or unsubstituted acyloxy, cyano, nitro, carboxy, substituted or unsubstituted alkoxycarbonyl, substituted or unsubstituted alkenyloxycarbonyl, substituted or unsubstituted alkynyloxycarbonyl, substituted or unsubstituted alkylsulfinyl, substituted or unsubstituted alkenylsulfinyl, substituted alkylsulfinyl

or unsubstituted, substituted or unsubstituted alkylsulfonyl, substituted or unsubstituted alkenylsulfonyl, substituted or unsubstituted alkylsulfonyl, substituted or unsubstituted carbamoyl, substituted or unsubstituted thiocarbamoyl, substituted or unsubstituted sulfamoyl, a substituted carbocyclic group or unsubstituted, substituted or unsubstituted carbocyclyloxy, substituted or unsubstituted carbocyclyloxycarbonyl, substituted carbocyclylsulfinyl

or unsubstituted, substituted or unsubstituted carbocyclylsulfonyl, a substituted or unsubstituted heterocyclic group, substituted or unsubstituted heterocyclyloxy, substituted or unsubstituted heterocyclyloxycarbonyl, substituted or unsubstituted heterocyclylsulfinyl, substituted or unsubstituted heterocyclylsulfonyl, excluding the compounds

image8

[Chemical Formula 12]

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wherein ring A 'and ring B are each independently a substituted or unsubstituted carbocycle or a substituted or unsubstituted heterocycle, Z is -L1-N (R8) -L2-, L1 and L2 are, each one independently, a bond, substituted or unsubstituted alkylene, substituted or unsubstituted alkenylene or substituted or unsubstituted alkynylene; and R8 is hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted acyl, its pharmaceutically acceptable salt or a solvate thereof. When Z is "-L1-N (R8) -L2-", then "L1" joins ring B and "L2" joins ring A ', respectively.

(2) The compound according to any of items (1), (1-1) and (1-2), in which ring A is [Chemical Formula 13]

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(10)

The compound according to any one of items (1), (1-1), (1-2), (2) to (4), (5-1) to (5-6) and (6) to (9), wherein R2a and R2b are both hydrogen, its pharmaceutically acceptable salt or a solvate thereof.

(eleven)

A pharmaceutical composition comprising the compound according to any one of items (1), (1-1), (1-2), (2) to (4), (5-1) to (5-6) and (6) to (10), its pharmaceutically acceptable salt or a solvate thereof as an active ingredient.

(12)

A pharmaceutical composition having BACE1 inhibitory activity, which comprises the compound according to any one of items (1), (1-1), (1-2), (2) to (4), (5-1 ) to (5-6) and (6) to (10), its pharmaceutically acceptable salt or a solvate thereof as an active ingredient.

(14)

The compound according to any one of items (1), (1-1), (1-2), (2) to (4), (5-1) to (5-6) and (6) to (10), its pharmaceutically acceptable salt or a solvate thereof for use in a method to inhibit the activity of BACE1.

(fifteen)

Use of a compound according to any one of items (1), (1-1), (1-2), (2) to (4), (5-1) to (5-6) and (6 ) to (10), its pharmaceutically acceptable salt, or solvate thereof for the manufacture of a medicament to inhibit the activity of BACE1.

(17)

Use of a compound according to any one of items (1), (1-1), (1-2), (2) to (4), (5-1) to (5-6) and (6 ) to (10), its pharmaceutically acceptable salt, or solvate thereof for the manufacture of a medicament for treating or preventing diseases induced by the production, secretion or deposition of amyloid β proteins.

(18)

A compound according to any one of items (1), (1-1), (1-2), (2) to (4), (5-1) to (5-6) and (6) to (10), its pharmaceutically acceptable salt, or solvate thereof for use in the treatment or prevention of diseases induced by the production, secretion or deposition of amyloid β proteins.

(twenty)

Use of a compound according to any one of items (1), (1-1), (1-2), (2) to (4), (5-1) to (5-6) and (6 ) to (10), your pharmaceutically acceptable salt or solvate thereof to make a medicament for treating or preventing Alzheimer's disease.

(twenty-one)

A compound according to any one of items (1), (1-1), (1-2), (2) to (4), (5-1) to (5-6) and (6) to (10), its pharmaceutically acceptable salt or solvate thereof for use in the treatment or prevention of Alzheimer's disease.

(22)

A method, a system, an apparatus, a kit or the like for the manufacture of the compound according to any one of items (1), (1-1), (1-2), (2) to (4), (5-1) to (5-6) and (6) to (10), its pharmaceutically acceptable salt or a solvate thereof.

(2. 3)

A method, a system, an apparatus, a kit or the like to prepare a pharmaceutical composition comprising the compound according to any one of items (1), (1-1), (1-2), (2) a (4), (5-1) to (5-6) and (6) to (10), its pharmaceutically acceptable salt or a solvate thereof.

(25)

A pharmaceutical composition according to item (11) or (12) for the treatment or prevention of a disease induced by the production, secretion or deposition of amyloid β proteins.

(26)

A pharmaceutical composition according to item (11) or (12) to treat or prevent Alzheimer's disease. [Effect of the Invention].

The compound of the present invention is useful as an agent for treating or preventing disease induced by the production, secretion or deposition of β-amyloid proteins, such as Alzheimer's disease. [How to Carry Out the Invention]

In the specification, the "halogen" includes fluorine, chlorine, bromine and iodine.

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In the specification, the "alkyl" includes linear or branched alkyl of a number of carbons from 1 to 15, for example a number of carbons from 1 to 10, for example a number of carbons from 1 to 6 and, for example, a number of carbons from 1 to 3. Examples include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec.-butyl, tert-butyl, n-pentyl, isopentyl, neopentyl, hexyl, isohexyl, n -heptyl, isoheptyl, n-octyl, isooctyl, n-nonyl and n-decyl.

The alkyl portions in "alkoxy", "haloalkyl", "hydroxyalkyl", "haloalkoxy", "hydroxy-alkoxy", "alkoxycarbonyl", "haloalkoxycarbonyl", "alkylamino", "aminoalkyl", "alkoxyalkoxy", "alkoxyalkenyloxy", "alkoxyalkynyl", "alkylcarbonyl", "carbamoyl", "hydroxyalkylcarbamoyl", "alkoxyimino", "alkylthio", "alkylsulfonyl", "alkylsulfonylamino", "alkylsulfonylalkylamino", "alkylsulfonylimino", "alkylsulfinylaminolamino" "," alkylsulfamoyl "," alkylsulfinyl "," carbocyclylalkyl "," carbocyclylalkoxy "," carbocyclylalkoxycarbonyl "," carbocyclylalkylamino "," carbocyclylalkylcarbamoyl "," cycloalkylalkyl "," cycloalkylalkyl "alkyloalkyl" cycloalkylalkyl " "arylalkyl", "arylalkoxy", "arylalkylamino", "arylalkoxycarbonyl", "arylalkylcarbamoyl", "heterocyclylalkyl", "heterocyclylalkoxy", "heterocyclylalkylamino", "heterocyclylalkoxycarbonyl" and "heterocyclic "alkylcarbamoyl" are the same as the "alkyl" above.

"Substituted or unsubstituted alkyl" may be substituted with one or more substituents selected from an α substituent group.

As used herein, the substituent group α is a group consisting of halogen, hydroxy, alkoxy, haloalkoxy, hydroxyalkoxy, alkoxyalkoxy, acyl, acyloxy, carboxy, alkoxycarbonyl, amino, acylamino, alkylamino, imino, hydroxyimino, alkoxyimino, alkylthio, carbamoyl, alkylcarbamoyl, hydroxyalkylcarbamoyl, sulfamoyl, alkylsulfamoyl, alkylsulfinyl, alkylsulfonylamino, alkylsulfonylalkyl amino, alkylsulfonylimino, alkylsulfinylamino, alkylsulfinylalkyl alkylamino, alkylsulfinylimino, cyano, heterocyclic group, a heterocyclic group of which is a heterocyclic group, a heterocyclic group of which is a heterocyclic group, a heterocyclic group of which is a heterocyclic group, a heterocyclic group of which is a heterocyclic group, a heterocyclic group with a heterocyclic group one or more substituents selected from halogen, alkyl, hydroxy and alkoxy.

Examples of the substituents "substituted or unsubstituted alkoxy", "substituted or unsubstituted alkoxycarbonyl", "substituted or unsubstituted alkylthio", "substituted or unsubstituted alkylsulfonyl" and "substituted or unsubstituted alkylsulfinyl" are one or more selected from the substituent α group mentioned above.

Examples of "haloalkyl" are trifluoromethyl, fluoromethyl and trichloromethyl.

Examples of "haloalkoxy" are trifluoromethoxy, fluoromethoxy, trichloromethoxy.

The term "alkylidene" includes a divalent group of the above "alkyl" and examples are methylidene, ethylidene, propylidene, isopropylidene, butylidene, pentylidene and hexylidene.

The term "alkenyl" includes linear or branched alkenyl of a carbon number from 2 to 15, for example a number of carbons from 2 to 10, for example a number of carbons from 2 to 6 and, for example, a number of carbons 2 to 4, which has one or more double bonds in any available position. Examples include vinyl, allyl, propenyl, isopropenyl, butenyl, isobutenyl, prenyl, butadienyl, pentenyl, isopentenyl, pentadienyl, hexenyl, isohexenyl, hexadienyl, heptenyl, octenyl, nonenyl, decenyl, undecenyl, dodecenyl, tridecenyl and tetradecentayl.

The alkenyl portions in "alkenyloxy", "alkenyloxycarbonyl", "carbonyl", "alkoxyalkenyloxy", "alkenylsulfonyl" "alkenylamino", "alkenylthio" and "alkenyl sulfinyl" are the same as the "alkenyl" above.

The term "alkynyl" includes a linear or branched alkynyl of a carbon number of 2 to 10, preferably a carbon number of 2 to 8, more preferably a carbon number of 3 to 6 having one or more triple bonds in the optional positions. Examples include ethynyl, propynyl, butynyl, pentinyl, hexinyl, heptinyl, octinyl, noninyl and decinyl. These can also have a double link in any available position.

Alkynyl portions in "alkoxyalkynyl", "alkynyloxy", "alkynyloxycarbonyl", "alkynylcarbonyl", "alkoxyalkyloxy", "alkynylthio", "alkylsulfinyl", "alkylsulfonyl" and "alkylamino" are the same as the "alkynyl" above.

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Examples of the substituent of "substituted or unsubstituted alkenyloxycarbonyl", "substituted or unsubstituted alkenylsulfinyl", "substituted or unsubstituted alkenyl", "substituted or unsubstituted alkenyloxy", "substituted or unsubstituted alkenylthio", "substituted or unsubstituted alkenyl sulfonyl" "," substituted or unsubstituted alkynyl "," substituted or unsubstituted alkynyloxy "," substituted or unsubstituted alkynylthio "," substituted or unsubstituted alkynyloxycarbonyl "," substituted or unsubstituted alkynylsulfinyl "and" substituted or unsubstituted alkynylsulfonyl "are" one or more substituents selected from the group α substituent mentioned above.

Examples of the substituent in "substituted or unsubstituted amino", "substituted or unsubstituted carbamoyl", "substituted or unsubstituted thiocarbamoyl" and "substituted or unsubstituted sulfamoyl" are one or two substituents selected from alkyl, acyl, hydroxy, alkoxy , alkoxycarbonyl, carbocyclic group and heterocyclic group.

The term "acyl" includes formyl, alkylcarbonyl of a number of carbons from 1 to 10, alkenylcarbonyl of a number of carbons from 2 to 10, alkynylcarbonyl of a number of carbons from 2 to 10, carbocyclylcarbonyl and heterocyclylcarbonyl. Examples are formyl, acetyl, propionyl, butyryl, isobutyryl, valeryl, pivaloyl, hexanoyl, acryloyl, propiolilo, methacryloyl, crotonoyl, benzoyl, cyclohexanecarbonyl, pyridinecarbonyl, furancarbonyl, thiophenecarbonyl, benzotiazolcarbonilo, pyrazinecarbonyl, piperidinecarbonyl, and thiomorpholino.

The acyl portions in "acyloxy" and "acylamino" are the same as the "acyl" above.

Examples of the "substituted or unsubstituted acyl" and "substituted or unsubstituted acyloxy" substituents are one or more substituents selected from the α substituent group. The parts of the carbocyclylcarbonyl and heterocyclylcarbonyl ring may be substituted with one or more substituents selected from alkyl, substituent group α and alkyl substituted with one or more substituents selected from substituent group α.

The term "carbocyclic group" includes cycloalkyl, cycloalkenyl, aryl and non-aromatic condensed carbocyclyl.

The term "cycloalkyl" includes a carbocyclic group of a number of carbons from 3 to 10, for example a number of carbons from 3 to 8 and, for example, a number of carbons from 4 to 8. Examples are cyclopropyl, cyclobutyl, cyclopentyl , cyclohexyl, cycloheptyl, cyclooctyl, cyclononyl and cyclodecyl.

The cycloalkyl portions in "cycloalkylalkyl", "cycloalkyloxy", "cycloalkylalkoxy", "cycloalkylthio", "cycloalkylamino", "cycloalkylalkylamino" "cicloalquilsulfamoilo", "cycloalkylsulfonyl", "cycloalkylcarbamoyl", "cicloalquilalquilcarbamoílo" "cycloalkylalkoxycarbonyl" and "cycloalkyloxycarbonyl "are the same as the" cycloalkyl "above.

The term "cycloalkenyl" includes a group having one or more double bonds at the positions optionally in the "cycloalkyl" ring above. Examples are cyclopropenyl, cyclobutenyl, cyclopentenyl, cyclohexenyl, cycloheptenyl, cyclooctenyl and cyclohexadienyl.

The term "aryl" includes phenyl, naphthyl, antryl and phenanthryl. A specific example is phenyl.

The term "non-aromatic condensed carbocyclic group" includes non-aromatic groups in which two or more cyclic groups selected from the above "cycloalkyl", "cycloalkenyl" and "aryl" are condensed. Examples are indanyl, indenyl, tetrahydronaphthyl and fluorenyl.

The carbocycle portions in "non-aromatic carbocycle" are the same as "cycloalkyl", "cycloalkenyl" and "condensed non-aromatic carbocyclic group". Examples are cyclopropane, cyclobutane, cyclopentane, cyclohexane, cycloheptane, cyclooctane, cyclononane, cyclodecane, cyclopropene, cyclobutene, cyclopentene, cyclohexene, cycloheptene and cyclooctene.

The carbocycle portions in "carbocycle", "carbocyclyloxy", "carbocyclylalkyl", "carbocyclylalkoxy", "carbocyclylalkoxycarbonyl", "carbocyclylthio", "carbocyclylamino", "carbocyclyl-alkylamino", "carbocyclylcarbonyloxycarbonylalkylcarbonylalkylcarbonylalkylcarbonylalkylcarbonylalkylcarbonylalkylcarbonylalkyl" "," carbocyclyl alkylcarbamoyl "," carbocyclyloxycarbonyl "," carbocyclylsulfinyl "and" carbocyclylsulfonyl "are the same as those of the" carbocyclic group "above.

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wherein the A 'ring and the B ring are each independently substituted or unsubstituted carbocycle or L1, L2 and L3 are each independently a bond, substituted or unsubstituted alkylene, substituted alkenylene

5 or unsubstituted or substituted or unsubstituted alkynylene, = W1 is = O, = S or = NR9, W2 is O, S or N (R5), R8 is hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, alkynyl substituted or unsubstituted or substituted or unsubstituted acyl, R9 is hydrogen, hydroxy, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted alkynyl or

10 unsubstituted or substituted or unsubstituted acyl, when ring A is (i), then the constituent carbon atom of L1 and the constituent carbon atom of L2, or the constituent carbon atom of L1 and the nitrogen atom of W2 may be connected with substituted or unsubstituted alkylene to form a ring, when ring A is (ii), then the constituent carbon atom of L1 and the constituent carbon atom of

15 L2, or the nitrogen atom of W2 and the carbon atom constituting L2 can be connected with substituted or unsubstituted alkylene to form a ring, when the ring A is (iii), then two nitrogen atoms of W2 can be connected with substituted alkylene

or unsubstituted to form a ring, when ring A is (vi), then the carbon atom constituting L1 and the carbon atom constituting

20 L2 may be connected by substituted or unsubstituted alkylene to form a ring, p is 1 or 2, and when multiple L3, multiple W2 or multiple R9 are present, each of them can be independently different. Specific examples are as follows:

25 [Chemical Formula 23]

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[Chemical Formula 24]

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wherein L is each independently a bond, substituted or unsubstituted alkylene, substituted or unsubstituted alkenylene or substituted or unsubstituted alkynylene, the T-ring is a carbocycle optionally substituted with one or a few groups selected from the substituent group α, or a heterocycle optionally substituted with one or a few groups selected from the α group, and those and other symbols are the same as defined above.

More specific examples are the following:

[Chemical Formula 25]

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in which each of the symbols is as defined above. [Chemical Formula 26]

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in which each of the symbols is as defined above.

Other examples of the substituent of "substituted carbocycle", "substituted or unsubstituted carbocycle", "heterocycle

5 substituted or unsubstituted "," substituted or unsubstituted benzene "," substituted or unsubstituted pyridine "," substituted or unsubstituted pyrimidine "and" substituted or unsubstituted pyrazine "in ring A, ring A 'and ring B include: a group selected from the substituent group α such as halogen, hydroxy, alkoxy, acyl, acyloxy, carboxy, alkoxycarbonyl, carbamoyl, amino, cyano, alkylamino and / or alkylthio; alkyl substituted with one or more groups selected from the substituent group α , hydroxyimino and alkoxyimino, in which

The substituent is, for example, halogen, hydroxy, alkoxy and / or alkoxycarbonyl, or unsubstituted alkyl; aminoalkyl substituted with one or more groups selected from the α substituent group; wherein the substituent is, for example, acyl, alkyl and / or alkoxy; alkenyl substituted with one or more substituents selected from the α substituent group, wherein the substituent is, for example, alkoxycarbonyl, halogen and / or halogenoalkoxycarbonyl, or unsubstituted alkenyl;

Alkynyl substituted with one or more substituents selected from the substituent group α, in which the substituent is, for example, alkoxycarbonyl or unsubstituted alkynyl; alkoxy substituted with one or more substituents selected from the

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α substituent group, in which the substituent is, for example, halogen, carbamoyl, alkylcarbamoyl and / or hydroxyalkylcarbamoyl; alkoxyalkoxy substituted with one or more substituents selected from the α substituent group; alkenyloxy substituted with one or more substituents selected from the α substituent group, wherein the substituent is, for example, halogen, hydroxy, amino and / or alkylamino, or unsubstituted alkenyloxy; alkoxyalkenyloxy substituted with one or more substituents selected from the α substituent group; alkynyloxy substituted with one or more substituents selected from the substituent group α, wherein the substituent is, for example, halogen and / or hydroxy or unsubstituted alkynyloxy; alkoxyalkyloxy substituted with one or more groups selected from the α substituent group; alkylthio substituted with one or more substituents selected from the substituent group α, or substituted alkylthio; alkenylthio substituted with one or more substituents selected from the substituent group α, or unsubstituted alkenylthio; alkynylthio substituted with one or more substituents selected from the substituent group α, or unsubstituted alkynylthio; alkylamino substituted with one or more substituents selected from the substituent group α; alkenylamino substituted with one or more substituents selected from the α substituent group; alkylamino substituted with one or more substituents selected from the α substituent group; aminooxy substituted with one or more substituents selected from the substituent group α and alkylidene, or unsubstituted aminooxy; acyl substituted with one or more substituents selected from the substituent group α; alkylsulfonyl substituted with one or more substituents selected from the substituent group α, or substituted alkylsulfonyl; alkylsulfinyl substituted with one or more substituents selected from the substituent group α, or unsubstituted alkylsulfinyl; alkylsulfamoyl substituted with one or more substituents selected from the α substituent group; a carbocyclic group such as cycloalkyl and aryl, substituted with one or more substituents selected from the substituent group α, azide, alkyl and haloalkyl; a heterocyclic group substituted with one or more substituents selected from the substituent group α, azide, alkyl and haloalkyl; carbocyclylalkyl such as cycloalkylalkyl and arylalkyl, substituted with one or more substituents selected from the substituent group α, azide, alkyl and haloalkyl, or unsubstituted carbocyclylalkyl; heterocyclylalkyl substituted with one or more substituents selected from the substituent group α, azide, alkyl and haloalkyl, or substituted heterocyclylalkyl; carbocyclyloxy such as cycloalkyloxy and aryloxy, substituted with one or more substituents selected from the substituent group α, azide, alkyl and haloalkyl, or unsubstituted carbocyclyloxy; heterocyclyloxy substituted with one or more substituents selected from the substituent group α, azide, alkyl and haloalkyl, or unsubstituted heterocyclyloxy; carbocyclylalkoxy such as cycloalkylalkoxy and arylalkoxy, substituted with one or more substituents selected from the substituent group α, azide, alkyl and haloalkyl, or unsubstituted carbocyclylalkoxy; heterocyclylalkoxy substituted with one or more substituents selected from the substituent group α, azide, alkyl and haloalkyl, or unsubstituted heterocyclylalkoxy; carbocyclylalkoxycarbonyl such as cycloalkylalkoxycarbonyl and arylalkoxycarbonyl, substituted with one or more substituents selected from the substituent group α, azide, alkyl and haloalkyl, or unsubstituted carbocyclylalkoxycarbonyl such as cycloalkylalkoxycarbonyl and arylalkoxycarbonyl; heterocyclylalkoxycarbonyl substituted with one or more substituents selected from the substituent group α, azide, alkyl and haloalkyl, or unsubstituted heterocyclylalkoxycarbonyl; carbocyclylthio such as cycloalkylthio and arylthio, substituted with one or more substituents selected from the substituent group α, azide, alkyl and haloalkyl, or unsubstituted carbocyclylthio such as cycloalkylthio and arylthio; heterocyclyl substituted with one or more substituents selected from the substituent group α, azide, alkyl and haloalkyl, or unsubstituted heterocyclyl; carbocyclylamino such as cycloalkylamino and arylamino, substituted with one or more substituents selected from the substituent group α, azide, alkyl and haloalkyl, or unsubstituted carbocyclylamino such as cycloalkylamino and arylamino; heterocyclylamino substituted with one or more substituents selected from the substituent group α, azide, alkyl and haloalkyl, or unsubstituted heterocyclylamino; carbocyclylalkylamino such as cycloalkylalkylamino and arylalkylamino, substituted with one or more substituents selected from the substituent group α, azide, alkyl and haloalkyl or unsubstituted carbocyclylalkylamino such as cycloalkylalkylamino and arylalkylamino; heterocyclylalkylamino substituted with one or more substituents selected from the substituent group α, azide, alkyl and haloalkyl, or unsubstituted heterocyclylalkylamino; carbocyclylsulfamoyl such as cycloalkylsulfamoyl and arylsulfamoyl, substituted with one or more substituents selected from the substituent group α, azide, alkyl and haloalkyl, or unsubstituted carbocyclylsulfamoyl; heterocyclylsulfamoyl substituted with one or more substituents selected from the substituent group α, azide, alkyl and haloalkyl, or unsubstituted heterocyclylsulfamoyl;

22

carbocyclylsulfonyl such as cycloalkylsulfonyl and arylsulfonyl, substituted with one or more substituents selected from the substituent group α, azide, alkyl and haloalkyl, or unsubstituted carbocyclylsulfonyl such as cycloalkylsulfonyl and arylsulfonyl; heterocyclylsulfonyl substituted with one or more substituents selected from the substituent group α, azide, alkyl and

Haloalkyl, or unsubstituted heterocyclylsulfonyl; carbocyclylcarbamoyl such as cycloalkylcarbamoyl and arylcarbamoyl, substituted with one or more substituents selected from the substituent group α, azide, alkyl and haloalkyl, or unsubstituted carbocyclylcarbamoyl such as cycloalkylcarbamoyl and arylcarbamoyl; heterocyclylcarbamoyl substituted with one or more substituents selected from the substituent group α, azide, alkyl and

Haloalkyl, or unsubstituted heterocyclylcarbamoyl; carbocyclyl alkylcarbamoyl such as cycloalkylalkylcarbamoyl and arylalkylcarbamoyl, substituted with one or more substituents selected from the substituent group α, azide, alkyl and haloalkyl, or unsubstituted carbocyclyl alkylcarbamoyl such as cycloalkylalkylcarbamoyl and arylalkylcarbamoyl; heterocyclyl alkylcarbamoyl substituted with one or more substituents selected from the substituent group α, azide,

Alkyl and haloalkyl, or unsubstituted heterocyclyl alkylcarbamoyl; carbocyclyloxycarbonyl such as cycloalkyloxycarbonyl and aryloxycarbonyl, substituted with one or more substituents selected from the substituent group α, azide, alkyl and haloalkyl, or unsubstituted carbocyclyloxycarbonyl such as cycloalkyloxycarbonyl and aryloxycarbonyl; heterocyclyloxycarbonyl substituted with one or more substituents selected from the substituent group α, azide, alkyl

20 and haloalkyl, or unsubstituted heterocyclyloxycarbonyl; halogen substituted alkylenedioxy, or unsubstituted alkylenedioxy; oxo; and azide.

The aforementioned ring of ring A and ring B each may be substituted with one or more substituents selected from each other.

In the specification, examples of the substituent of "unsubstituted carbocycle", "substituted or unsubstituted benzene", "substituted or unsubstituted heterocycle", "substituted or unsubstituted pyridine", "substituted or unsubstituted pyrimidine" and "substituted pyrazine or unsubstituted "in ring A 'and ring B include halogen, cyano, hydroxy, nitro, carboxy, alkyl substituted with one or more substituents selected from the substituent group α, unsubstituted alkyl,

30 alkoxy substituted with one or more substituents selected from the substituent group α, unsubstituted alkoxy, amino substituted with one or more substituents selected from the substituent group α, unsubstituted amino, carbamoyl substituted with one or more substituents selected from the substituent group α, carbamoyl substituted, alkoxycarbonyl substituted with one or more substituents selected from the substituent group α, and unsubstituted alkoxycarbonyl.

Examples of substituents other than "Z-ring B" of "substituted or unsubstituted carbocycle" or "substituted or unsubstituted heterocycle" in ring A include halogen, alkyl, alkenyl, alkynyl, alkoxy, alkenyloxy, alkynyloxy

or cyano.

Examples of the substituents of "substituted or unsubstituted carbocycle," "substituted or unsubstituted benzene" or "substituted or unsubstituted heterocycle" on the A 'ring include halogen.

Examples of the substituents of "substituted or unsubstituted carbocycle", "substituted or unsubstituted heterocycle", "substituted or unsubstituted pyridine", "substituted or unsubstituted pyrimidine" or "substituted or unsubstituted pyrazine" in ring B include halogen, alkyl, alkenyl, alkynyl, alkoxy, alkenyloxy, alkynyloxy or cyano.

Examples of the substituents of "substituted or unsubstituted carbocyclic group", "substituted or unsubstituted carbocyclylthio", "substituted or unsubstituted carbocyclyloxycarbonyl", "substituted or unsubstituted heterocyclyl", "substituted or unsubstituted carbocyclyloxy", "carbocyclylsulfinyl substituted or unsubstituted "," substituted or unsubstituted carbacyclylsulfonyl "," substituted or unsubstituted carbocycle "," substituted or unsubstituted heterocyclyl "," substituted or unsubstituted heterocyclyloxy "," substituted or unsubstituted heterocyclylthioxy " substituted "," substituted or unsubstituted heterocyclylsulfinyl "," substituted or unsubstituted heterocyclylsulfonyl "," substituted heterocycle

or unsubstituted "," substituted or unsubstituted cyclopentane "," substituted or unsubstituted cyclopentene "," cyclohexane

"Substituted or unsubstituted" and "substituted or unsubstituted cyclohexene" in another other than ring A., ring A 'and ring B above include one or more substituents selected from the substituent group α, unsubstituted alkyl and alkyl substituted with one or more substituents selected from the substituent group α.

2. 3

image19

image20

[Chemical Formula 29]

25

image21

[Chemical Formula 30]

26

image22

These groups may be substituted with one or more selected from alkyl substituted with one or more selected from the substituent group α, unsubstituted alkyl and alkyl substituted with one or more substituents selected from the substituent group α at any available position.

Examples of groups in which

[Chemical Formula 31]

image23

in which each symbol is as defined in section (1), and Q 'is substituted or unsubstituted carbocycle, include [Chemical Formula 32]

image24

These groups may be substituted with one or more selected from alkyl substituted with one or more selected from the substituent group α, unsubstituted alkyl and alkyl substituted with one or more substituents selected from the substituent group α at any available position.

The phrase "Rza and Rzb, together with the carbon atom to which they are attached, can form a substituted or unsubstituted non-aromatic carbocycle or a substituted or unsubstituted non-aromatic heterocycle" include the following examples.

[Chemical Formula 33]

28

image25

image26

These groups may be substituted with one or more selected from alkyl substituted with one or more selected from the substituent group α, unsubstituted alkyl and alkyl substituted with one or more substituents selected from the substituent group α at any available position.

5 In the specification, the term "solvate" includes, for example, solvates with organic solvents and hydrates. It can be prepared according to known methods. Examples of solvate include a solvate with acetone, 2butanol, 2-propanol, ethanol, ethyl acetate, tetrahydrofuran or diethyl ether. For example, it includes a non-toxic and water-soluble hydrate or a solvate such as a solvate with ethanol. In the case that a hydrate or solvate is formed, the compound or salt can be coordinated with any number of solvate molecules or water molecules.

The compound of the formula (I) includes a pharmaceutically acceptable salt. Examples include salts with alkali metals such as lithium, sodium or potassium; alkaline earth metals such as calcium; magnesium; transition metals such as zinc or iron; ammonium; organic bases; and amino acids; or salts with inorganic acids such as hydrochloric acid, sulfuric acid, nitric acid, hydrobromic acid, phosphoric acid or hydroiodic acid; and organic acids such as acetic acid, trifluoroacetic acid, citric acid, lactic acid, tartaric acid, oxalic acid, acid

Maleic, fumaric acid, mandelic acid, glutaric acid, malic acid, benzoic acid, phthalic acid, benzenesulfonic acid, p-toluenesulfonic acid, methanesulfonic acid or ethanesulfonic acid. Specific examples are hydrochloric acid, phosphoric acid, tartaric acid and methanesulfonic acid. These salts can be formed by ordinary methods.

In addition, the compound of the formula (I) is not limited to a specific isomer, but includes all possible

20 isomers, such as keto-enol isomers, imine-enamine isomers, diastereoisomers, optical isomers and rotation isomers; and racemate. For example, the compound of the formula (I) in which R2a is hydrogen, includes the following tautomers.

[Chemical Formula 35]

30

image27

as Pd / C, in the presence or absence of a base. Other suitable methods for preparing tritiated compounds can be found in Isotopes in the Physical and Biomedical Sciences, Vol. I, Labeled Compounds (Part A) Chapter 6 (1987). Compounds marked with 14C can be prepared by using starting materials that have a 14C carbon.

5 (General Procedures)

The compounds of formulas (I) and (Ia) to (If) of the present invention can be prepared by the methods described below. In the following steps, when there is a substituent that interferes with the reaction, e.g. For example, hydroxy, mercapto, amino, formyl, carbonyl, carboxy, the substituent is protected by the method as described in advance in Protective Groups in organic Synthesis, and Theodora W Greene (John Wiley & Sons), and the

10 protecting group can be separated at a convenient stage.

1) Synthesis of Compound (Ia)

[Chemical Formula 38]

image28

15 where each symbol is as defined above.

Stage 1.

Compound b can be prepared by adding a titanium reagent such as chlorotitanium triisopropoxide to enolate, which is obtained by reacting an objective ester such as ethyl propionate in the presence of a base such as lithium diisopropylamide in a solvent such as toluene, dichloromethane and tetrahydrofuran, or a mixed solvent of

20 by adding a compound that can be prepared by known methods and reacting at -80 ° C to 30 ° C, preferably -80 ° C to 0 ° C, for 0.1 to 24 hours, preferably 0, 1 to 12 hours

Stage 2

Compound c can be prepared by adding a Grignard reagent such as methylmagnesium bromide that is commercially available or can be prepared by known methods or a reducer such as borane, sodium borohydride and lithium aluminum hydride in Compound b in a solvent such as dioxane,

32

image29

image30

image31

image32

image33

image34

image35

image36

image37

image38

image39

image40

image41

image42

image43

image44

image45

image46

image47

image48

image49

image50

image51

image52

image53

image54

image55

image56

image57

image58

image59

image60

image61

image62

image63

image64

image65

image66

image67

image68

image69

image70

image71

image72

image73

image74

image75

image76

No.

Structure NMR (solvent: ascending order of offset value)

 image77

image78 image79

I-16

image80 image81

I-17

image82 image83

I-18

image84 image85

I-19

image86 image87

[Table 1-4]

No.

Structure . Structure

I-20

image88 I-28 image89

81 82 [Table 1-5]

No.

Structure . Structure

 image90

image91 image92 image93

I-21

image94 I-29 image95

I-22

image96 I-30 image97

I-23

image98 I-31 image99

I-24

image100 I-32 image101

I-25

image102 I-33 image103

I-26

image104 I-34 image105

No.

Structure . Structure

 image106

image107 image108 image109

I-27

image110 I-35 image111

No.

Structure  No. Structure

I-36

image112 I-44 image113

I-37

image114 I-45 image115

I-38

image116 I-46 image117

I-39

image118 I-47 image119

83

image120

image121

image122

image123

image124

image125

image126

image127

image128

image129

Claims (11)

image 1 image2 image3 image4 image5 image6 image7 image8 image9 image10 image11 R3a R4a wherein and are the same as defined in claim 1, its pharmaceutically acceptable salt or a solvate thereof.

eleven.

The compound according to any one of claims 6 to 10, wherein -Z-is -C (= O) N (R8) -, its pharmaceutically acceptable salt or a solvate thereof.

12. The compound according to any one of claims 6 to 11, wherein the A 'ring is substituted or unsubstituted benzene, and the B ring is substituted or unsubstituted pyridine, substituted or unsubstituted pyrimidine or substituted or unsubstituted pyrazine substituted, its pharmaceutically acceptable salt or a solvate thereof.

13.

The compound according to any one of claims 1 to 9, 11 and 12, wherein R4a and R4b are both hydrogen, its pharmaceutically acceptable salt or a solvate thereof.

14.

The compound according to any one of claims 1 to 3 and 5 to 13, wherein R1 is unsubstituted C1 to C3 alkyl, its pharmaceutically acceptable salt or a solvate thereof.

fifteen.

The compound according to any one of claims 1 to 14, wherein R2a and R2b are both hydrogen, its pharmaceutically acceptable salt or a solvate thereof.

16. A pharmaceutical composition comprising the compound according to any one of claims 1 to 15, its pharmaceutically acceptable salt or a solvate thereof as an active ingredient. 17. The pharmaceutical composition according to claim 16, wherein the composition has BACE1 inhibitory activity. 18. The compound according to any one of claims 1 to 15, its pharmaceutically acceptable salt 20 or a solvate thereof for use in a method for inhibiting the activity of BACE1. 19. The compound according to any one of claims 1 to 15, its pharmaceutically acceptable salt or a solvate thereof where the formula is represented by: image12 20. A compound of formula (I): 104 image13 wherein ring A is a substituted carbocycle or a substituted or unsubstituted heterocycle, R1 is substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted acyl, cyano, carboxy, substituted alkoxycarbonyl or unsubstituted, substituted or unsubstituted alkenyloxycarbonyl, substituted or unsubstituted alkynyloxycarbonyl or substituted or unsubstituted carbamoyl, substituted or unsubstituted thiocarbamoyl, a substituted or unsubstituted carbocyclic group, a substituted or unsubstituted heterocyclic group, R2a and R2b are each independently, hydrogen, substituted or unsubstituted alkyl, substituted acyl or unsubstituted, substituted or unsubstituted alkoxycarbonyl or substituted or unsubstituted carbamoyl, image14 wherein Rza and Rzb are each independently hydrogen, halogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted alkoxy, substituted or unsubstituted alkenyloxy, substituted or unsubstituted alkynyloxy substituted, substituted or unsubstituted alkylthio, substituted alkenylthio or unsubstituted, substituted or unsubstituted alkynylthio, substituted or unsubstituted acyl, carboxy, substituted alkoxycarbonyl 15 or unsubstituted, substituted or unsubstituted alkenyloxycarbonyl, substituted or unsubstituted alkynyloxycarbonyl, substituted or unsubstituted amino, substituted or unsubstituted carbamoyl, substituted or unsubstituted thiocarbamoyl, a substituted or unsubstituted carbocyclic group, carbocyclyl substituted or unsubstituted, carbocyclic substituted or unsubstituted, substituted or unsubstituted carbocyclylalkyl. substituted or unsubstituted carbocyclylalkoxy, substituted or unsubstituted carbocyclyloxycarbonyl, a substituted or unsubstituted heterocyclic group, substituted or unsubstituted heterocyclyloxy, 20 substituted or unsubstituted heterocyclylthio, substituted or unsubstituted heterocyclylalkyl, unsubstituted or substituted heterocyclylalkoxy, substituted or unsubstituted heterocyclyloxycarbonyl, or Rza and Rzb, together with the carbon atom to which they are attached, may form a substituted or non-aromatic carbocycle substituted or a substituted non-aromatic heterocycle or unsubstituted, R3a, R3b, R3c, R4a, R4b and R4c are each independently hydrogen, halogen, hydroxy, alkyl substituted or not 25 substituted, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted alkoxy, substituted or unsubstituted alkynyloxy or substituted or unsubstituted alkynyloxy, substituted or unsubstituted alkylthio, substituted or unsubstituted alkenylthio, substituted or unsubstituted alkynylthio , substituted or unsubstituted acyl, substituted or unsubstituted acyloxy, cyano, nitro, carboxy, substituted or unsubstituted alkoxycarbonyl, substituted or unsubstituted alkenyloxycarbonyl, substituted or unsubstituted alkynyloxycarbonyl, substituted or unsubstituted amino, carbamoyl 30 substituted or unsubstituted, substituted or unsubstituted thiocarbamoyl, substituted or unsubstituted sulfamoyl, substituted or unsubstituted alkylsulfinyl, substituted or unsubstituted alkenylsulfinyl, substituted or unsubstituted alkylsulfinyl, substituted or unsubstituted alkylsulfonyl, substituted or unsubstituted alkylsulfonyl or unsubstituted, a substituted or unsubstituted carbocyclic group, substituted or unsubstituted carbocyclyloxy, substituted or unsubstituted carbocyclylthio, substituted or unsubstituted carbocyclylalkyl, substituted or unsubstituted carbocyclylalkoxy, 35 substituted or unsubstituted carbocyclyloxycarbonyl, substituted or unsubstituted carbocyclylsulfinyl, substituted or unsubstituted carbocyclylsulfonyl, a substituted or unsubstituted heterocyclic group, substituted or unsubstituted heterocyclyloxy, substituted or unsubstituted heterocyclyl, substituted or unsubstituted heterocyclyl , substituted or unsubstituted heterocyclyloxycarbonyl, substituted or unsubstituted heterocyclylsulfinyl or substituted or unsubstituted heterocyclylsulfonyl, R3a and R3b, together with the carbon atom to which they are attached, can form a substituted or unsubstituted carbocycle

or a substituted or unsubstituted heterocycle, R4a and R4b, together with the carbon atom to which they are attached, can form a substituted or unsubstituted carbocycle

or a substituted or unsubstituted heterocycle,

105 the Q ring is a substituted or unsubstituted carbocycle, or a substituted or unsubstituted heterocycle, the broken line a, the broken line b and the broken line c each independently means the presence or absence of a bond, when a broken line a means the presence of a link, then R3b and R4b are absent, when the broken line b means the presence of a link, then R3c is absent when the broken line c means the presence of a link, then R4c is absent, Y1 e Y2 are, each independently, -C (R5) (R6) -, -C (R5) =, -N (R7) -, -N =, -S-, -SO-, -SO2-u -O- , Y3 and Y4 are, each independently, -C (R5) (R6) -, N (R7) -, -S-, -SO-, -SO2-u -O-, R5 and R6 are, each independently , hydrogen, halogen, hydroxy, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted alkoxy, substituted alkenyloxy

or unsubstituted, substituted or unsubstituted alkynyloxy, substituted or unsubstituted alkylthio, substituted or unsubstituted alkenylthio, substituted or unsubstituted alkynylthio, substituted or unsubstituted acyl, substituted or unsubstituted acyloxy, cyano, nitro, carboxy, substituted or unsubstituted alkoxycarbonyl substituted, substituted or unsubstituted alkenyloxycarbonyl, alkynyloxycarbonyl, substituted or unsubstituted amino, substituted or unsubstituted carbamoyl, substituted or unsubstituted thiocarbamoyl, substituted or unsubstituted sulfamoyl, substituted or unsubstituted alkylsulfinyl, substituted alkenylsulfinyl

or unsubstituted, substituted or unsubstituted alkylsulfinyl, substituted or unsubstituted alkylsulfonyl, substituted or unsubstituted alkenylsulfonyl, substituted or unsubstituted alkylsulfonyl, a substituted or unsubstituted carbocyclic group, substituted or unsubstituted carbocyclyloxy, substituted or unsubstituted carbocyclyl, substituted or unsubstituted carbocyclyl or unsubstituted, substituted or unsubstituted carbocyclylalkoxy, substituted or unsubstituted carbocyclyloxycarbonyl, substituted or unsubstituted carbocyclylsulfinyl, substituted or unsubstituted carbocyclylsulfonyl, a substituted or unsubstituted heterocyclyl group, substituted or unsubstituted heterocyclyl or substituted heterocyclyl or unsubstituted, substituted or unsubstituted heterocyclylalkoxy, substituted or unsubstituted heterocyclyloxycarbonyl, substituted or unsubstituted heterocyclylsulfinyl, substituted or unsubstituted heterocyclylsulfonyl and R7 is hydrogen, halogen, hi droxy, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted alkoxy, substituted or unsubstituted alkenyloxy, substituted alkynyloxy

or unsubstituted, substituted or unsubstituted acyl, substituted or unsubstituted acyloxy, cyano, nitro, carboxy, substituted or unsubstituted alkoxycarbonyl, substituted or unsubstituted alkenyloxycarbonyl, substituted or unsubstituted alkynyloxycarbonyl, substituted or unsubstituted alkylsulfinyl, substituted or alkenylsulfinyl substituted, substituted alkylsulfinyl

or unsubstituted, substituted or unsubstituted alkylsulfonyl, substituted or unsubstituted alkenylsulfonyl, substituted or unsubstituted alkylsulfonyl, substituted or unsubstituted carbamoyl, substituted or unsubstituted thiocarbamoyl, substituted or unsubstituted sulfamoyl, a substituted carbocyclic group or unsubstituted, substituted or unsubstituted carbocyclyloxy, substituted or unsubstituted carbocyclylthio, substituted or unsubstituted carbocyclylalkyl, substituted or unsubstituted carbocyclylalkoxy, substituted or unsubstituted carbocyclyloxycarbonyl, substituted or unsubstituted carbocyclyl, substituted heterocyclic or unsaturated carbocyclic or unsubstituted, substituted or unsubstituted heterocyclyloxy, substituted or unsubstituted heterocyclylthio, substituted or unsubstituted heterocyclylalkyl, substituted or unsubstituted heterocyclylalkoxy, substituted or unsubstituted heterocyclyloxycarbonyl, heterocyclylsulfinyl substituted or unsubstituted or substituted or unsubstituted heterocyclylsulfonyl,

the "substituted carbocycle" and "substituted or unsubstituted heterocycle" substituents on ring A, ring A 'and ring B "substituted or unsubstituted alkyl", "substituted or unsubstituted alkoxy", "substituted or unsubstituted alkoxycarbonyl", "substituted or unsubstituted alkylthio", "substituted or unsubstituted alkylsulfonyl", "substituted or unsubstituted alkylsulfinyl", "alkenyl substituted or unsubstituted "," substituted or unsubstituted alkenyloxy "," substituted or unsubstituted alkenyloxycarbonyl "," substituted or unsubstituted alkenylthio "," substituted or unsubstituted alkenylsulfinyl "," substituted or unsubstituted alkenyl sulfonyl "," substituted or alkynyl unsubstituted "," substituted or unsubstituted alkynyloxy "," substituted or unsubstituted alkynylthio "," substituted or unsubstituted alkynyloxycarbonyl "," substituted or unsubstituted alkynylsulfinyl "," substituted or unsubstituted alkylsulfonyl "," substituted or unsubstituted alkylene "," substituted or unsubstituted alkenylene "," substituted or unsubstituted alkynylene "," substituted or unsubstituted acyl "," substituted or unsubstituted acyloxy "," amino substituted or unsubstituted "," substituted or unsubstituted carbamoyl "," substituted or unsubstituted thiocarbamoyl "," substituted or unsubstituted sulfamoyl ", the substituents of" substituted or unsubstituted carbocyclic group "," substituted or unsubstituted carbocyclylthio ", "substituted or unsubstituted carbocyclyloxycarbonyl", "substituted or unsubstituted carbocyclyloxy", "substituted or unsubstituted carbocyclylsulfinyl", "substituted or unsubstituted carbocyclylsulfonyl", "substituted or unsubstituted heterocyclyloyl", "heterocyclyl substituted or unsubstituted" substituted or unsubstituted "," substituted or unsubstituted heterocyclyloxycarbonyl "," substituted or unsubstituted heterocyclylsulfinyl "and" substituted or unsubstituted heterocyclylsulfonyl " in another than ring A, ring A 'and ring B are, if present, the same as defined in claim 1, excluding compounds wherein 106 image15 and ring A is image16 wherein ring A 'and ring B are each independently a substituted or unsubstituted carbocycle or a substituted or unsubstituted heterocycle, Z is -L1' -N (R8) -L2'-, L1 'and L2 'are, each independently, a link; substituted or unsubstituted alkylene, wherein the substituent is one or more selected from halogen, alkoxy, haloalkoxy, hydroxyalkoxy, alkoxyalkoxy, acyl, acyloxy, carboxy, alkoxycarbonyl, amino, acylamino, alkylamino, imino, hydroxyimino, alkoxyimino, alkylthio, carbamoyl, alkylcarbamoyl, hydroxyalkylcarbamoyl, sulfamoyl, alkylsulfamoyl, alkylsulfinyl, alkylsulfonylamino, alkylsulfonylalkylamino, alkylsulfonylimino, alkylsulfinylamino, alkylsulphinyl alkylamino, alkylsulfinylimino, cyano, nitro, a carbocyclic group and an optionally substituted heterocyclic group selected from halogen, alkyl, hydroxy and alkoxy; substituted or unsubstituted alkenylene, wherein the substituent is one or more selected from halogen, alkoxy, haloalkoxy, hydroxyalkoxy, alkoxyalkoxy, acyl, acyloxy, carboxy, alkoxycarbonyl, amino, acylamino, alkylamino, imino, hydroxyimino, alkoxyimino, alkylthio, carbamoyl, alkylcarbamoyl, hydroxyalkylcarbamoyl, sulfamoyl, alkylsulfamoyl, alkylsulfinyl, alkylsulfonylamino, alkylsulfonylalkylamino, alkylsulfonylimino, alkylsulfinylamino, alkylsulphinyl alkylamino, alkylsulfinylimino, cyano, nitro, a carbocyclic group and an optionally substituted heterocyclic group selected from halogen, alkyl, hydroxy and alkoxy; or substituted or unsubstituted alkynylene, wherein the substituent is one or more selected from halogen, alkoxy, haloalkoxy, hydroxyalkoxy, alkoxyalkoxy, acyl, acyloxy, carboxy, alkoxycarbonyl, amino, acylamino, alkylamino, imino, hydroxyimino, alkoxyimino, alkylthio, carbamoyl , alkylcarbamoyl, hydroxyalkylcarbamoyl, sulfamoyl, alkylsulfamoyl, alkylsulfinyl, alkylsulfonylamino, alkylsulfonylalkylamino, alkylsulfonylimino, alkylsulfinylamino, alkylsulfinyl alkylamino, alkylsulfinylimino, cyano, nitro, a carbocyclic group and one heterocyclic group, each of which is optionally substituted with one heterocyclic group substituents selected from halogen, alkyl, hydroxy and alkoxy; and R8 is hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl or substituted or unsubstituted acyl, its pharmaceutically acceptable salt or solvate thereof for use in the treatment and / or prevention of Alzheimer's type dementia, Down syndrome, memory impairment, prion disease (Creutzfeldt-Jakob disease), mild cognitive impairment ( MCI), Dutch type of hereditary cerebral hemorrhage with amyloidosis, cerebral amyloid angiopathy, other degenerative dementia, mixed dementia with Alzheimer's disease and vascular type, dementia with Parkinson's disease, dementia with progressive supranuclear paralysis, dementia with Basal degeneration corticotropin, Alzheimer's disease with diffuse Lewy body disease, age-related macular degeneration, Parkinson's disease, or amyloid angiopathy. 21. The compound for use according to claim 20, represented by the formula (Iα): 107 image17 image18 image19